The present invention is concerned with novel broad-spectrum azole antifungals and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
Systemic fungal infections in man are relatively rare in temperate countries and many of the fungi that can become pathogenic normally live commensally in the body or are common in the environment. However, the past few decades have witnessed an increasing incidence of numerous life-threatening systemic fungal infections world-wide and these now represent a major threat to many susceptible patients, particularly those already hospitalized. Most of the increase can be attributed to improved survival of immunocompromised patients and the chronic use of antimicrobial agents. Moreover, the flora typical of many common fungal infections is also changing and this is presenting an epidemiological challenge of increasing importance. Patients at greatest risk include those with impaired immune functioning, either directly as a result of immunosuppression from cytotoxic drugs or HIV infection, or secondary to other debilitating diseases such as cancer, acute leukaemia, invasive surgical techniques or prolonged exposure to antimicrobial agents. The most common systemic fungal infections in man are candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis.
Antifungals such as ketoconazole, itraconazole and fluconazole are employed for the treatment and prophylaxis of systemic fungal infections in immunocompromised patients. However, concern is growing about fungal resistance to some of these agents, especially these with a more narrow spectrum, e.g. fluconazole. Worse still, it is recognized in the medical world that about 40% of the people suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration. This inability is due to the fact that such patients are in coma or suffer from severe gastroparesis. Hence the use of insoluble or sparingly soluble antifungals such as itraconazole, that are difficult to administer intravenously, is heavily impeded in said group of patients.
Consequently, there is a need for new antifungals, preferably broad-spectrum antifungals, against which there is no existing resistance and which can be administered intravenously. Preferably the antifungal should also be available in a pharmaceutical composition suitable for oral administration. This enables the physician to continue treatment with the same drug after the patient has recovered from the condition which required intravenous administration of said drug.
U.S. Pat. No. 4,267,179 discloses heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles useful as antifungal agents. Said patent encompasses itraconazole, which is now available as a broadspectrum antifungal on a world-wide basis.
U.S. Pat. No. 4,916,134 teaches 4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]triazolones having improved antimicrobial properties.
U.S. Pat. No. 4,791,111 discloses derivatives of [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles, structurally related to some of the compounds of the present invention, which are taught to have favourable anti-microbial properties. A particular compound disclosed herein is cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]-phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazol-3-one, said compound being a stereoisomeric mixture of all possible enantiomers and diastereomers having the cis configuration at the 1,3-dioxolane ring.
WO 93/19061 discloses the [2R-[2xcex1,4xcex1,4(R*)]], [2R-[2xcex1,4xcex1,4(S*)]], [2S-[2xcex1,4xcex1,4(S*)]] and [2S-[2xcex1,4xcex1,4(R*)]] stereospecific isomers of itraconazole, which are taught to have greater water solubility than the respective diastereomeric mixtures thereof.
WO 95/19983 discloses derivatives of [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles, structurally related to some of the compounds of the present invention, which are taught to be water-soluble antimicrobial agents.
WO 95/17407 discloses tetrahydrofuran antifungals as well as WO 96/38443 and WO 97/00255. The latter two publications discloses tetrahydrofuran antifungals, which are taught to be soluble and/or suspendible in an aqueous medium suitable for IV, containing substitution groups readily convertible in vivo into hydroxy groups.
The present invention concerns novel compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein
xe2x80x94Axe2x80x94Bxe2x80x94 forms a bivalent radical of formula:
xe2x80x94Nxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a),
xe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(b),
xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(c),
wherein one hydrogen atom in the radicals (a) and (b) may be replaced with a C1-6alkyl-radical and up to two hydrogen atoms in radical (c) may be replaced by a C1-6alkyl-radical;
L represents the acyl moiety of an amino acid, and thus xe2x80x94Oxe2x80x94L represents an amino acid ester group;
D is a radical of formula 
wherein
X is N or CH;
R1 is halo;
R2 is hydrogen or halo.